Whole-genome doubling in breast cancer promotes immune evasion (From Darryl Leja, National Human Genome Research Institute, NIH via Flickr).Whole-genome doubling (WGD), which is frequently detected in solid tumors, is associated with poor patient outcomes. Using mouse models of breast cancer with WGD, Foidart and colleagues find that one potential explanation for this is that WGD promotes immune evasion. WGD+ tumors escape CD8+ T cells due to a reduction in antigen presentation. This occurs because WGD+ tumors have higher levels of succinate, which reduces the activity of the histone lysine demethylase KDM6, leading to higher histone H3 lysine 27 trimethylation (H3K27me3) and thereby reduction in expression of transcriptional regulators of antigen-presentation genes. Consistent with this, inhibition of the H3K27me3 methyltransferase PRC2 enhances antigen presentation and reduces WGD+ tumor growth.Foidart P, …, Polyak K. Cancer Cell 2026 May 07;DOI:10.1016/j.ccell.2026.04.007.Salt-inducible kinases suppress T-cell antitumor function in high-grade serous ovarian cancer (From Huza90 via Wikimedia Commons).Malignant ascites from patients with high-grade serous ovarian cancer (HGSOC) are highly immunosuppressive. Using a high-throughput drug screen, Dong and colleagues identify salt-inducible kinases (SIKs) as contributors to T-cell suppression by malignant ascites from HGSOC patients. In preclinical ovarian tumor mouse models, pharmacologic inhibition of SIK and T cell–intrinsic Sik2 and Sik3 knockout increase cytokine production, tumor microenvironment remodeling, and tumor control. Combination therapy of PD-1 blockade with SIK inhibition improves survival, supporting the addition of SIK inhibition to combination immune checkpoint blockade therapies.Dong H, …, Glimcher LH. Nat Immunol 2026 May 20;27,1237–1252.A cytotoxic CD39+CD49a+CD103+ NK-cell subpopulation exhibits antitumoral function (From NIAID via Wikimedia Commons).Which subpopulation of natural killer (NK) cells has the greatest antitumor potential? Using multiomic analyses, Horowitz and colleagues generate a population of cytotoxic, tissue-resident–like CD49a+CD103+ NK cells (ctrNK), characterized by expression of CD39, by coculturing peripheral human NK cells with head and neck squamous cell carcinoma cell lines and IL15. Compared with conventionally activated peripheral NK cells, these ctrNK cells display enhanced cytolytic activity, tumor infiltration, and improved control of solid tumors upon adoptive transfer, supporting the use of ex vivo differentiated and expanded ctrNK cells in adoptive cell therapy for solid tumors.Horowitz NB, …, Sunwoo JB. Sci Trans Med 2026 May 06;18,eadw5567.Intratumoral ipilimumab administration reduces treatment-related adverse events compared to intravenous administration (from DBCLS via Wikimedia Commons).Immune checkpoint therapies are usually administered intravenously and can result in severe treatment-related adverse events. In a multicenter randomized phase 1b trial with 61 individuals with untreated metastatic skin cancer, Tselikas and colleagues compared intravenous (IV) nivolumab combined with either a standard dose of IV ipilimumab or a tenfold lower dose of intratumoral (IT) ipilimumab. The trial met its primary endpoint, with significantly reduced incidence of severe treatment-related adverse events at 6 months in the IT arm. Immune profiling of baseline tumor biopsies indicates that the presence of Tregs and M2 macrophages determines durable clinical benefit for combined anti-CTLA4 and anti–PD-1 checkpoint blockade therapy, regardless of anti-CTLA4 administration route.Tselikas L, …, Marabelle A. Nature 2026 Apr 29; DOI:10.1038/s41586-026-10341-w.SCLC BBB-like vasculature gate impedes T-cell infiltration (from Yale Rosen via Wikimedia Commons).Why neuroendocrine cancers such as small cell lung cancer (SCLC) rarely respond to immune checkpoint inhibitors (ICI) is unclear. Through analysis of patient samples, Wang and colleagues observed a unique vasculature in SCLC and other neuroendocrine cancers that resembles the blood-brain barrier (BBB). In a mouse model of SCLC, this BBB-like vasculature serves as a gate, preventing T-cell infiltration. Mechanistically, the BBB-like vascular gate is induced by SCLC cells via an ASCL1–IGFBP5–IGF1R axis. Targeting IGFBP5 genetically or inhibiting IGF1R pharmacologically increases CD8+ T-cell infiltration and enhances anti–PD-1 efficacy. The data highlight a mechanism limiting ICI efficacy in neuroendocrine cancers and an approach to overcome this.Wang Y, …, Chen C. Cell 2026 May 07;DOI:10.1016/j.cell.2026.04.017.Epigenetic reprogramming of polyamine biosynthesis reinvigorates exhausted T cells (from pxhere.com).Exhausted T cells (TEX) have distinct epigenetic programs. In a screen of epigenetic-based therapeutics, Wu and colleagues found that bromodomain and extra-terminal motif (BET) inhibitors reinvigorate TEX isolated from malignant pleural effusions from patients with lung cancer by reprogramming metabolic pathways in the T cells. Specifically, BET inhibition activates polyamine biosynthesis by increasing chromatin accessibility at genes key to polyamine biosynthesis, including ornithine decarboxylase 1 (ODC1). The ability of BET inhibition to reinvigorate TEX, reduces malignant pleural effusion in a mouse model of lung cancer. The observation that ODC1 expression is associated with favorable clinical outcomes in patients with lung cancer highlights the clinical relevance of the data.Wu Y-C, …, Tsai H-C. Nat Immunol 2026 May 12;27,1268–1281.
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